Emerging Medical Devices for Minimally Invasive Cell Therapy Eoin D. O'Cearbhaill, PhD, Kelvin S. Ng, BS, Jeffrey M. Karp, PhD  Mayo Clinic Proceedings  Volume 89, Issue 2, Pages 259-273 (February 2014) DOI: 10.1016/j.mayocp.2013.10.020 Copyright © 2014 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure 1 Current and proposed (in italics) injection sites and methods for cell therapy. The delivery methods highlighted are for minimally invasive (clockwise from top left) neural, cardiovascular, diabetes, and orthopedic cell therapy. Images adapted from Servier Medical Art. Mayo Clinic Proceedings 2014 89, 259-273DOI: (10.1016/j.mayocp.2013.10.020) Copyright © 2014 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure 2 Current trends in therapeutic targets and delivery methods for cell therapy. A subset of cell therapies (69 considered) undergoing clinical trials or under review by the US Food and Drug Administration were identified in Pharmaceutical Research and Manufacturers of America's Medicines in Development: Biologics, 2013 Report.11 Information on therapeutic targets and delivery methods was obtained through company websites and ClinicalTrials.gov. Mayo Clinic Proceedings 2014 89, 259-273DOI: (10.1016/j.mayocp.2013.10.020) Copyright © 2014 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure 3 Graphical representation of several approaches considered for cell delivery to the heart. The ideal method of administration would be highly targeted and minimally invasive. Mayo Clinic Proceedings 2014 89, 259-273DOI: (10.1016/j.mayocp.2013.10.020) Copyright © 2014 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure 4 Common problems with minimally invasive delivery of cells. These issues are multifactorial and can occur before, during, and after delivery. A, Cells in suspension tend to settle, leading to uneven distribution of cells on delivery. B, Cells may attach to the delivery system. C, Cells tend to form aggregates that might impair their function and ease of administration. D, Cell health will depend on the viscosity of the injected fluid, the cell size, the inner diameter and surface roughness of the needle, the ratio of needle diameter to reservoir (syringe barrel) diameter, the rate of infusion, etc. E, Underdosing. Blind insertion can (F) miss the target site or (G) lead to backpressure, and leakage during infusion into a closed space could lead to cell damage and poor delivery. H, Improper sealing of the needle track after delivery can lead to escape of the transplanted cells, particularly in muscle tissue, where compressive forces are higher. I, Heterogeneous tissue structure may cause needles to deflect in an unpredictable manner away from the target site. J, A large target site may require multiple injections, increasing invasiveness. K, The injected fluid tends to travel along the path of least resistance (eg, along the fascia), which could cause cells to be dispersed away from the target site. Furthermore, cells may tend to migrate after delivery. L, Clumps and inconsistent cell dispersion may result from delivery of a cell scaffold or carrier if the rate of infusion or scaffold gelation is poorly controlled. Mayo Clinic Proceedings 2014 89, 259-273DOI: (10.1016/j.mayocp.2013.10.020) Copyright © 2014 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure 5 Approaches for isolating transplanted cells from the host immune system. For type 1 diabetes therapy, through either microencapsulation or macroencapsulation, a semipermeable barrier allows the diffusion of glucose and oxygen into, and insulin, glucagon, and waste products out of, the transplanted glucose-responsive insulin-secreting cells while restricting their interaction with the host's immune system. The table provides a summary of the advantages and disadvantages of standard methods of microencapsulation and macroencapsulation (++, strong advantage; +, advantage; −, disadvantage). Longevity of immunoisolation: Microencapsulation biomaterials, such as alginate, have shown promise as immunologic barriers between the host and the transplanted cells; however, the long-term integrity of these biodegradable coatings in vivo is not well understood. Macroencapsulation devices tend to use nonbiodegradable membrane materials that will preserve immunoisolation for the duration of implantation. Diffusion distance consistency: Microencapsulation of individual cells or islets results in a very thin capsule and a minimal path of diffusion in all directions (eg, 22 μm79) compared with the less consistent diffusion path associated with the thicker membranes (eg, >30 μm80) of macroencapsulation devices, which may have cell populations that are several layers thick. Cell populations in devices can experience heterogeneous diffusion gradients and are prone to developing necrotic cores. Durability: Macroencapsulation devices are relatively robust when compared with microencapsulated cells. Engraftment site retention: Microencapsulated cells can have poor initial cell retention and engraftment at target sites, whereas macroencapsulation devices can be inserted, through subcutaneous implantation, in a controlled manner that will lead to a consistent microenvironment for the transplanted encapsulated cells. Retrievability: If necessary, unlike microencapsulated cells, macroencapsulation devices can be retrieved. Ease of use: Depending on the preferred site of injection/implantation, both methods can be suited for minimally invasive delivery. Mayo Clinic Proceedings 2014 89, 259-273DOI: (10.1016/j.mayocp.2013.10.020) Copyright © 2014 Mayo Foundation for Medical Education and Research Terms and Conditions